Oesophageal atresia (OA) is a congenital defect associated with additional malformations in 30-70% of the cases. In particular, OA is a component of the VACTERL association. Since some major features of the VACTERL association, including conotruncal heart defect, radial aplasia, and anal atresia, have been found in patients with microdeletion 22q11.2 (del(22q11.2)), we have screened for del(22q11.2) by fluorescent in situ hybridisation (FISH) in 15 syndromic patients with OA. Del(22q11.2) was detected in one of them, presenting with OA, tetralogy of Fallot, anal atresia, neonatal hypocalcaemia, and subtle facial anomalies resembling those of velocardiofacial syndrome. The occurrence of del(22q11.2) in our series of patients with OA is low (1/15), but this chromosomal anomaly should be included among causative factors of malformation complexes with OA. In addition, clinical variability of del(22q11.2) syndrome is further corroborated with inclusion of OA in the list of the findings associated with the deletion.
- microdeletion 22q11
- oesophageal atresia
- VACTERL association
- velocardiofacial syndrome
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Oesophageal atresia (OA) is a congenital defect which can occur as an isolated malformation or in association with additional malformations in 30-70% of patients.4-12 Specifically, OA is a component of the VACTERL association (V=vertebral defects, A=anorectal defects, C=cardiac defects, TE=oesophageal atresia with Tracheo-oEsophageal fistula, R=renal anomalies, radius aplasia, rib anomalies, L=limb defects), occurring in 20 to 67% of patients with this multiple anomaly association.13-15 Some major clinical features of the VACTERL association have been found in patients with del(22q11.2), including conotruncal heart defect,15 radial aplasia,16 renal anomalies,17 and anal atresia.18 However, OA has never been described in patients with del(22q11.2). We have screened for del(22q11.2) by fluorescent in situ hybridisation (FISH) in order to evaluate the prevalence of the deletion in syndromic patients with OA.
Patients and methods
From January 1995 to September 1997, 15 patients with syndromic OA and normal standard chromosomes were referred to the Department of Medical Genetics of our hospital for genetic evaluation. All patients were clinically examined and checked for additional malformations by two clinical geneticists. There were eight males and seven females. Their mean age was 2.1 years (age range 0.1 to 10.8 years). Clinical features of the patients included in the study are summarised in table 1. OA type III (OA with distal tracheo-oesophageal fistula) was found in 13 patients and OA type I (OA without tracheo-oesophageal fistula) in two. Six patients had multiple anomalies that fulfilled the criteria for VACTERL association. Velocardiofacial syndrome was diagnosed in one case, CHARGE (C=coloboma, H=heart defect, A=atresia choanae, R=retarded growth, G=genital hypoplasia, E=ear anomalies) association in one, and Goldenhar syndrome in another one. For the remaining six patients, a diagnosis of a recognisable genetic condition was not reached.
FISH analysis showed 22q11.2 hemizygosity in one of the 15 (6.7%) patients analysed. Del(22q11.2) was sporadic, as shown by normal FISH analysis in the unaffected parents. The deleted patient was a female neonate with OA associated with tetralogy of Fallot, anorectal malformation (rectovestibular fistula), and subtle facial anomalies resembling those of velocardiofacial syndrome (table 1). In addition, hypocalcaemia was present in the first days of life. At 7 months of age, weight was 5800 g (3rd centile), length 65 cm (10th centile), and head circumference 43 cm (10th centile). A normal thymic shadow was detected on chest x ray and echocardiographic study. T lymphocyte numbers were slightly below the normal range.
To our knowledge, the present case is the first report of OA with del(22q11.2). The association of OA, tetralogy of Fallot, and anal atresia presented by our patient had first suggested the clinical diagnosis of VACTERL association, but, subsequently, the coexistence of conotruncal heart defect, neonatal hypocalcaemia, T lymphocyte defect, and facial anomalies prompted the clinical diagnosis of velocardiofacial syndrome. We believe that careful clinical examination for evident or even subtle facial dysmorphism of velocardiofacial or DiGeorge syndrome21 22 is essential in patients with clinical features of VACTERL association, expecially those with conotruncal heart defect. Del(22q11.2) should be included among causative factors of malformation complexes with OA or other features of VACTERL association. In fact, radial aplasia, renal anomalies, and anal atresia are additional malformations found to be associated with del(22q11.2) in some cases.16-18 Clinical variability of del(22q11.2) is further supported by the present report, and OA is added to the list of clinical findings associated with the deletion. Nevertheless, the occurrence of del(22q11.2) in our series of patients with EA is low, and accurate evaluation for specific anomalies of velocardiofacial or DiGeorge syndromes can select patients for FISH analysis.